The present invention relates to polymeric materials which are dual stimuli-responsive (DSR) to changes in both the temperature and pH of a human body, and a process for preparing such materials.
An important ingredient for a drug delivery system (DDS) includes special materials for encapsulating or charging the active drug. Stimuli-responsive materials that have been used as such special materials up to now are described in Y. H. Bae, Controlled Drug Delivery: Challenges and Strategies, K. Park, Ed., Am. Chem. Soc., Chap. 8, pages 147-162, Washington, D.C. (1997).
Among the stimuli-responsive materials, poly(N-isopropylacrylamide) has been well known as a special polymer matrix for drug delivery because this polymer can exhibit a thermo-responsive property depending on the change of human body temperature. It also exhibits a physical property specific for the lower critical solution temperature (LCST).
Polymeric electrolytes obtained by polymerizing vinylic monomers having carboxyl acid, sulfonic acid, an amine or an ammonium group have been used as pH-responsive hydrogels such as described in Polyelectrolyte Gels; Properties, Preparation, and Applications,xe2x80x9d R. S. Harland and R. K. Prud""homme, Eds., ACS Symp. Series # 480, Am. Chem. Soc., Chap. 17, page 285, Washington, D.C. (1992).
Known xe2x80x9cintelligentxe2x80x9d polymeric materials having DSR property include a copolymer obtained by grafting a pH-responsive enzyme onto a thermo-responsive material. Problems associated with preparing existing DSR material include difficulty in control of the molecular weight of the hydrogel formed, wherein the molecular weight may determine drug delivery efficacy.
Accordingly, it is an object of the present invention to provide random or block hydrogel copolymers having both thermo- and pH-responsive properties.
Another object of the present invention is to provide a method for controlling the molecular weight of the random or block hydrogel copolymers, which affects both the thermo- and pH-responsive properties.
Other objects of the present invention will become apparent to those skilled in the art after having the benefit of this disclosure.
The present invention provides novel materials exhibiting DSR (dual stimuli-responsive) property such as both thermo and pH-responsive properties, and also covers a process of preparing these substances by atom transfer radical polymerization, wherein said process comprises the steps of: synthesizing sulfonamide-type vinylic monomers having pH-responsive properties; and, copolymerizing N-isopropylacrylamide or methylene bisacrylamide monomer having thermo-responsive property, with sulfonamide-type monomers to produce random or block copolymers exhibiting both pH-responsive and thermo-responsive properties.
As used herein, the term atom transfer radical polymerization (ATRP) also refers to xe2x80x9ccontrol/livingxe2x80x9d radical polymerization which is well described in the literature (T. E. Patten and K. Matyjaszewski, Adv. Mater., 10, 10:901, 1998).
The present invention provides a process for preparing hydrogels having both thermo- and pH-responsive properties with controlled molecular weights, which comprises the steps of:
(a) synthesizing sulfoneamide type of vinyl monomers having pH-responsive properties;
(b) preparing poly(N-isopropylacrylamide) or its copolymer with methylene bisacrylamide having thermo-responsive property; and
(c) random or block copolymerizing said pH-responsive monomers with thermo-responsive monomers; wherein said steps (b) and (c) are carried out by controlled/living radical polymerization using phosphine-based or amine-based transition-metal catalysts and alkyl halogen initiators.
The pH-responsive sulfoneamide type of styrene derivatives according to the present invention are monomers represented by the following formula (1) or (2). 
wherein,
R1 is selected from the group consisting of phenyl, isoxazole, acetyl, methizole, dimethoxine, diazine, methoxypyridazine, methazine, isomidine and pyridine.
The compound of the following formula (3) is prepared by following the procedures described in S. Y. Park and Y. H. Bae, Macromol. Rapid Commun., 20:269 (1999), and can be used as the (meth)acrylamide type monomer carrying a sulfonamide group of the present invention. 
wherein
R1 is defined as above and R2 is hydrogen or a methyl group.
The catalysts used in the present invention are the complexes of copper halide and the following ligands, bipyridine, iron halide and diimine, ruthenium halide and phosphines, nickel halide and phosphines, and the like. The preferred catalysts are the complexes of nickel halide and phosphines, iron halide and amine, and copper halide and amine.
The phosphines used in the present invention are bis(diphenylphosphino)ethane, bis(dimethylphosphino)ethane, bis(triphenyl) phosphine [(Ph3P)2], or bis(trimethyl) phosphine ([(CH3)3P]2), and the like.
The amines used in the present invention include 2,2xe2x80x2-bipyridine, pentamethyl-diethylenetriamine, tris[2-(dimethylamino)ethyl]amine; (Me)6 Tren, and the like.
Specifically, the phosphine-based nickel and iron catalysts include the compounds of the following formula (4) or (5) 
wherein
R1 to R5 are independently selected from the group consisting of methyl, phenyl, iso-propyl, tert-butyl and ethyl;
Mt is nickel or iron; X is chlorine or bromine; and n is an integer of 1 to 3.
The amine-based copper catalysts used in the present invention have amine-based ligands represented by the following formulas (6) to (8): 
wherein R represents H, 5-nonyl or n-heptyl. 
wherein R represents n-propyl or n-butyl. 
wherein n represents 1, 2 or 3.
Generally, alkyl halides are used as the initiators in the present invention.
The solvents used in the present invention include polar solvents, such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, distilled water, solvents containing halogens, lower alcohols, or the mixtures thereof; and non-polar solvents, such as hexane, toluene, benzene or cyclohexane.
According to the present invention, the block copolymers can be prepared in the suitable temperature range of xe2x88x9278xc2x0 C. to 150xc2x0 C., more suitably between xe2x88x9250xc2x0 C. to 30xc2x0 C.
The DSR hydrogels prepared according to the present invention are represented by the following formulas (9) to (14): 
wherein
R1 is selected from the group consisting of phenyl, isoxazole, acetyl, methizole, dimethoxine, diazine, methoxypyridazine, methazine, isomidine and pyridine;
R2 represents hydrogen or methyl;
m is 5 to 500, preferably 50 to 300;
n is 3 to 500, preferably 5 to 100; and
the ratio of y/x ranges from 2/98 to 8/92.
The present invention is further illustrated by the following examples, but such examples are not intended to limit the invention in any way.